Donepezil hydrochloride (I) is a reversible acetylcholinesterase inhibitor that has the following structure:

Donepezil (known as 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine)hydrochloride is an effective drug for treating dementia and Alzheimer's disease. The drug is administrated in the form of oral solid formulations such as 5 and 10 mg film coated tablets, capsules and granules and is given to the patients once daily.
The preparation of donepezil was described in several patents, for example: U.S. Pat. Nos. 4,895,841, 6,252,081, PCT Patent Application published as WO 97/22584, EP Patent 1386607 and others.
U.S. Pat. Nos. 5,985,864, 6,140,321, 6,245,911, U.S patent applications Publication Nos. 2004/0034057 and 2004/0229914, PCT Patent Application published as WO 2004/087660, and an article published in Indian Journal of Chemistry, Section B: Organic Chemistry including Medicinal Chemistry 44B(6), 1231-1235, 2005, which are incorporated by reference as if fully set forth herein, describe various amorphous and crystalline forms of donepezil hydrochloride
U.S. Pat. Nos. 5,985,864 and 6,140,321 describe five different crystalline forms of donepezil hydrochloride (including hydrates) as well as an amorphous donepezil hydrochloride. The different crystalline forms of donepezil hydrochloride described in these patents, may be prepared either by dissolving the salt in a polar solvent (such as methanol), while heating, and adding a less polar solvent (such as isopropyl ether) upon cooling, followed by filtration of the separated crystals, or by dissolving the base in a polar solvent (such as methanol) while heating and adding an alcoholic solution of concentrated hydrochloric acid followed by filtration of the separated crystals.
U.S. Pat. No. 6,245,911 describes three novel crystalline forms of donepezil hydrochloride (A, B and C) and the processes for their preparation.
US Patent Application Publication No. 2004/0034057 discloses a process for industrial production of a crystalline form of donepezil hydrochloride.
US Patent Application Publication No. 2004/0229914 discloses a novel crystalline form VI of donepezil hydrochloride and process for preparing of same.
US Patent Application Publication No. 2005/0107613 discloses three crystalline oxalate salts of donepezil and methods of their preparation.
PCT Patent Application published as WO 2004/099142 discloses crystalline forms of the hydrobromide salt of donepezil and processes for their preparation.
The detailed prior art shows that donepezil hydrochloride tends to appear in more than one crystalline form, each having different characteristic behavior. These different crystalline forms are known as polymorphs. While polymorphs have the same chemical composition, they differ in packing and geometrical arrangement, and exhibit different physical properties such as melting point, shape, color, hardness, bulk density, deformability, stability, dissolution, and the like.
Since each polymorph has different characteristic behavior, a major problem of using a crystalline polymorphic drug is associated with obtaining a reproducible solid form of the active pharmaceutical ingredient. An example of the limitations associated with polymorphs is the anti-epilepsy drug carbamazepine, in which only a specific crystalline form is allowed, because the US Pharmacopoeia dictates in the monograph the pharmaceutical use of only a specific crystalline form (characterized by its X-ray diffraction pattern). In addition, other health authorities require assurance for the correct crystalline form of the drug used as well.
One way of alleviating the problem, of obtaining reproducible solid forms of active pharmaceutical ingredients, is to use non-crystalline forms of these materials. On one hand the problem of having variety of crystalline forms does not exist. On the other hand, non-crystalline amorphous solids are known to have better dissolution. As a result one can expect a good, consistent availability of the active ingredient. Therefore, non-crystalline materials may be offered as a solution to this problem because when a material is amorphous, there cannot be polymorphism.
Normally such a non-crystalline form has a better solubility and faster dissolution rate, thus assuring good bioavailability.
The use of stable amorphous donepezil hydrochloride in pharmaceutical preparations is provided in U.S. Pat. No. 6,734,195 (to the present applicant). Stable pharmaceutical preparations containing amorphous donepezil hydrochloride are easily obtained according to the teachings of this application. In addition there is no change in the impurity content of the amorphous material stored at 40° C. after 3 and 6 months of storage at 75% relative humidity, and the highest impurity level is 0.1% with the total impurities level of 0.4%. These levels are exactly the initial values. There was no indication of chemical degradation of amorphous donepezil hydrochloride produced.
Another problem concerned with using crystalline donepezil is that the purification of the compound either by crystallizing the base or the hydrochloride salt, as taught in the literature, may require several crystallization steps to yield a pharmaceutically pure product and hence the process suffers from relatively low yields.
Since the existing crystallization methods of donepezil base and donepezil hydrochloride suffer from relatively low yields and unstable polymorphism, there is a recognizable need for a simple and efficient purifying process for obtaining a stable, amorphous donepezil hydrochloride in pharmaceutical grade purity. On the other hand, the crystallization of donepezil maleate proceeds with much better yields and affords better and consistent quality.
Thus, the present invention provides a process for obtaining pharmaceutically pure amorphous donepezil hydrochloride via crystallization of highly pure crude donepezil maleate, which yields pharmaceutically pure amorphous donepezil hydrochloride.